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1-Chloromethylpyrene: a reference skin sensitizer and genotoxin
J Ashby1, J E Gallagher, M Kohan
1ICI Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, Great Britain.
Mutation Research
|April 1, 1990
Summary
1-Chloromethylpyrene (1-CMP) is a potent mutagen and DNA-reactive compound. While inactive in mouse bone marrow assays, it shows significant skin toxicity and allergenicity, suggesting potential human skin carcinogenicity.
Area of Science:
- Environmental Chemistry
- Toxicology
- Molecular Biology
Background:
- 1-Chloromethylpyrene (1-CMP) serves as a model for electrophilic mutagens like those from benzo[a]pyrene.
- Understanding 1-CMP's reactivity is crucial for assessing risks associated with polycyclic aromatic hydrocarbons.
Purpose of the Study:
- To evaluate 1-CMP as a model mutagen and toxin.
- To assess its genotoxicity, DNA reactivity, and skin toxicity.
- To investigate its hydrolysis kinetics and potential as a human skin carcinogen.
Main Methods:
- Bacterial mutagenicity assays (Salmonella).
- DNA adduct formation assessed by 32P-postlabeling.
- In vivo mouse bone micronucleus assay.
- Skin toxicity evaluation: mitogenicity and local lymph node assay for contact allergenicity.
- Hydrolysis kinetics study.
Main Results:
- 1-CMP demonstrated mutagenicity in Salmonella ( > 100 pg/plate) and high DNA reactivity.
- It was inactive in the mouse bone micronucleus assay, likely due to rapid hydrolysis (t1/2 ≈ 23 min at 37°C).
- 1-CMP exhibited potent skin toxicity, acting as a mitogen and contact allergen in mice.
Conclusions:
- 1-CMP is a potent mutagen and DNA-reactive agent.
- Its rapid hydrolysis limits in vivo genotoxicity assessment via oral administration but highlights its potential as a skin toxin.
- 1-CMP is predicted to be a potent human skin carcinogen and contact allergen.